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Projekt Druckansicht

Ein molekulares Netzwerk der Interaktion von Leptin und Insulin im Hypothalamus als Schlüssel zum Verständnis der Pathogenese ernährungsbedingter Erkrankungen.

Antragsteller Dr. Alexander Tups
Fachliche Zuordnung Ernährungswissenschaften
Förderung Förderung von 2013 bis 2018
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 243471766
 
Erstellungsjahr 2017

Zusammenfassung der Projektergebnisse

Metabolic inflammation in the central nervous system might be causative for the development of overnutrition-induced metabolic syndrome and related disorders, such as obesity, leptin and insulin resistance, and type 2 diabetes. Aim of this proposal was to identify whether hypothalamic inflammation may interrupt the central network of leptin and insulin signalling and thereby contribute to the development of obesity and type 2 diabetes. We established that nutritive and genetic inhibition of the central pro-inflammatory IκB kinase β (IKKβ)/nuclear factor-κB (NF-κB) pathway in diet-induced obese (DIO)- or leptin-deficient mice improves metabolic impairments. Genetic inhibition of the IKKβ/NF-κB signaling pathway in the arcuate nucleus, via specific adeno-associated virus serotype 2-mediated overexpression of IκBα, which inhibits NF-κB nuclear translocation, attenuated HFD-induced body weight gain, body fat mass accumulation, increased energy expenditure, and reduced arcuate suppressor of cytokine signaling 3 expression (SOCS-3), suggesting that reversal of this process may enhance leptin signaling. One key question in metabolism research, which was also addressed in this proposal is whether leptin resistance is caused by hypothalamic inflammation, or whether hypothalamic inflammation is a consequence of leptin resistance because leptin acts also as a proinflammatory hormone. A loss of leptin sensitivity as determined by leptin’s ability to activate pSTAT3 in the arcuate nucleus occurred already within 24 hours of high fat feeding, well before body fat mass and circulating leptin levels increased, which coincides with the onset of hypothalamic inflammation suggesting this process is leading to leptin resistance rather than hyperleptinemia per se. Additionally, we also established that the evolutionary highly conserved WNT pathway plays a crucial role in the neuroendocrine regulation of body weight and exhibits a novel not yet identified leptin pathway.

Projektbezogene Publikationen (Auswahl)

 
 

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